Primary Sjogren's syndrome (pSS) is a chronic, inflammatory autoimmune disorder characterized by lymphocytic infiltration into exocrine glands. Hallmark features include salivary and lacrimal gland dysfunction, causing significant morbidity. pSS patients are at increased risk for serious clinical manifestations such as lymphoma and neurological disease. Widespread systemic manifestations are common and may include concurrent diagnoses with related autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and scleroderma. Clinical and genetic data suggest partial overlap in some aspects of underlying disease mechanisms between pSS and numerous other autoimmune diseases. The precise etiologic mechanisms that govern specificity for autoimmune mediated exocrinopathy in pSS are unknown. Genetic studies of pSS to date support the hypothesis that pSS is a complex genetic disorder, but have been limited to candidate gene approaches in small cohorts. As a result, the genetic architecture of this complex disease is largely unexplored. Identification of susceptibility genes in pSS is now feasible due to major advances in our understanding of variation in the human genome and development of powerful analytic tools. Preliminary data generated by our group using gene expression profiling and genome-wide association studies with pooled DNA approaches have identified several key biological pathways and hundreds of genes as high priority candidates for further evaluation. To more comprehensively identify and characterize susceptibility genes in pSS, we propose a multi-stage case-control genome-wide association study. In Stage I, we will perform a genome-wide association study in European-derived females using state of the art genotyping technology to assay over 500,000 single nucleotide polymorphisms (SNPs) in a cohort of 800 extensively characterized pSS patients for comparison with at least 3200 matched controls. A series of recently developed data analysis metrics will be applied to the data, including alignment with genome wide RNA transcript levels, to prioritize the top 1500 candidate SNPs. A Stage 2 replication study will be performed by testing the 1500 high priority SNPs that pass Stage I thresholds for association in an independent, European-derived female-only cohort of 1400 pSS cases and 1400 matched controls. In Stage 3, detailed analysis of candidate genes will include evaluation in additional ethnicities, with fine mapping, sequencing, and functional studies as warranted to define and characterize the causal variants. Identification of genes involved in pSS is likely to provide novel and important insight into the underlying causes of this common disorder. PUBLIC HEALTH REVELANCE: The goal of this large scale project is to identify genes that confer risk for developing Sjogren's Syndrome using a comprehensive genome wide approach. The resulting knowledge should generate novel opportunities for the development of improved diagnostic tools, biomarkers for monitoring disease, and innovative therapies for this complex disorder and other related autoimmune diseases.